Genetic Structure of IDDM1: Two Separate Regions in the Major Histocompatibility Complex Contribute to Susceptibility or Protection

Moghaddam, Payman Hanifi; Knijf, P. De; Roep, Bart O.; Auwera, Bart Van Der; Naipal, A.; Gorus, Frans; Schuit, Frans; Giphart, M. J.

doi:10.2337/diab.47.2.263

Cited by 52 publications

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“…We were not able to confirm the existence of relatively frequent DQB1*02-DRB1*03-D6S273, and DQB1*0302-DRB1*0401-D6S273 haplotypes that are associated with type 1 diabetes as reported in a Belgian case control study (Moghaddam et al 1998). Strong linkage disequilibrium was found, with D6S273*8 (140 bp) being predominantly present on both transmitted and non-transmitted DQ*02-DR*03 haplotypes, and D6S273*6 (136 bp) on DQ*0302-DR*0401 haplotypes.…”

Section: mentioning

confidence: 39%

“…In contrast, one case-control study of Belgian subjects matched for the high risk DQB1-DRB1 genotype reports an additional effect of the TNF region by analysing extended HLA-DQB1-DRB1 haplotypes with the microsatellite marker D6S273, which is located 130 kb centromeric of the TNF locus (Moggadaham et al 1998). More recently, Lie et al (1999) reported a trend of association at D6S273 using the Homozygous Parent Test, but the effect was not consistent with the D6S273 alleles implicated in the study of Moghaddam et al (1998).…”

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confidence: 99%

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Conditional ETDT analysis of the Human Leukocyte Antigen region in type 1 diabetes

Koeleman

Herr

Zavattari³

et al. 2000

Annals of Human Genetics

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Several studies have indicated that additional genes in the major histocompatibility complex (MHC) region, other than the class II genes HLA-DQB1 and -DRB1 (the IDDM1 locus), may contribute to susceptibility and resistance to type 1 diabetes. The relative magnitude of these non-DR\DQ effects is uncertain and their map location is unknown owing to the extraordinary linkage disequilibrium that extends over the 3.5 Mb of the MHC. The homozygous parent test has been proposed as a method for detection of additional risk factors conditional on HLA-DQB1 and -DRB1. However, this method is inefficient since it uses only parents homozygous for the primary disease locus, the DQB1-DRB1 haplotype. To overcome this limitation, Conditional ETDT was used in the present report to test for association conditional on the DQB1-DRB1 haplotype, thereby allowing all parents to be included in the analysis. First, we confirm in UK and Sardinian type 1 diabetic families that allelic variation at HLA-DRB1 has a very significant effect on the association of DQB1 and vice versa. The Conditional ETDT was then applied to the HLA TNF (tumour necrosis factor) region and microsatellite marker D6S273 region, both of which have been reported to contribute to IDDM1 independent of the HLA-DQB1-DRB1 genes. We found no evidence for a major role for either of these two regions in IDDM1. Combined genetic and biological studies in the last two decades have shown that alleles of the Correspondence :

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Section: mentioning

confidence: 39%

mentioning

confidence: 99%

Conditional ETDT analysis of the Human Leukocyte Antigen region in type 1 diabetes

Koeleman

Herr

Zavattari³

et al. 2000

Annals of Human Genetics

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“…10 Over the last years, a large body of evidence has accumulated, suggesting the presence of at least a second T1D locus (and another CD-associated gene) within or close to the MHC, and markers located within the HLA class II, III and I regions, as well as the extended class I region have been shown to influence the genetic susceptibility of developing T1D. [11][12][13][14][15][16] A recent report suggests that DR3-B8 does not confer increased risk to T1D compared to other less conserved DR3 chromosomes, 17 but, in contrast, there is evidence supporting a stronger contribution of DR3-B18 to the genetic susceptibility to T1D; indeed, several predisposing alleles of these HLA class II-independent genes are present in the DR3-B18 haplotype. 14,16 It can be inferred that particular DR3 CEHs carrying different variants of these riskmodifying genes would contribute unequally to the risk of developing one or another autoimmune disorders.…”

Section: Introductionmentioning

confidence: 99%

Conserved extended haplotypes discriminate HLA-DR3-homozygous Basque patients with type 1 diabetes mellitus and celiac disease

et al. 2006

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The major susceptibility locus for type 1 diabetes mellitus (T1D) maps to the human lymphocyte antigen (HLA) class II region in the major histocompatibility complex on chromosome 6p21. In southern European populations, like the Basques, the greatest risk to T1D is associated with DR3 homo-and heterozygosity and is comparable to that of DR3/DR4, the highest risk genotype in northern European populations. Celiac disease (CD) is another DR3-associated autoimmune disorder showing certain overlap with T1D that has been explained by the involvement of common genetic determinants, a situation more frequent in DR3-rich populations, like the Basques. As both T1D-and CD-associated HLA alleles are part of conserved extended haplotypes (CEH), we compared DR3-homozygous T1D and CD patients to determine whether CEHs were equally distributed between both disorders or there was a differential contribution of different haplotypes. We observed a very pronounced distribution bias (Po10 À5 ) of the two major DR3 CEHs, with DR3-B18 predominating in T1D and DR3-B8 in CD. Additionally, high-density single nucleotide polymorphism (SNP) analysis of the complete CEH [A*30-B*18-MICA*4-F1C30-DRB1*0301-DQB1*0201-DPB1*0202] revealed extraordinary conservation throughout the 4.9 Mbp analyzed supporting the existence of additional diabetogenic variants (other than HLA-DRB1*0301-DQB1*0201), conserved within the DR3-B18 CEH (but not in other DR3 haplotypes) that could explain its enhanced diabetogenicity.

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“…Nevertheless, the population frequency of DR3/4 genotype is still 10-20 times higher than the prevalence of type 1 diabetes associated with this genotype (1,7). DRB1 subtyping might change the risk of type 1 diabetes in the DQ high-risk population, even though it is assumed to be accounted for only 10% (7,8).…”

mentioning

confidence: 97%

“…DRB1 subtyping might change the risk of type 1 diabetes in the DQ high-risk population, even though it is assumed to be accounted for only 10% (7,8). This implies that additional protective genes and/or environmental factors influence susceptibility to the disease.…”

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confidence: 99%

MICA Polymorphism Is Associated With Type 1 Diabetes in the Korean Population

et al. 2001

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OBJECTIVE -Recent studies have demonstrated that MICA (major histocompatibility complex class I chain-related genes) on the short arm of the chromosome 6 are associated with susceptibility to various autoimmune diseases in Caucasians. The aim of our study was to investigate the role of MICA in type 1 diabetes susceptibility independent of the HLA DR-DQ polymorphism in genetically distinct Koreans. RESEARCH DESIGN AND METHODS -A total of 119 patients selected fromKorean Seoul type 1 diabetes registry and 134 nondiabetic unrelated control subjects were typed for exon 5 polymorphism of MICA in addition to HLA DR-DQ typing. A total of 52 simplex families of type 1 diabetes were also studied.RESULTS -The MICA microsatellite allele consisting of six repetitions of GCT/AGC (A6) was present at a significantly lower frequency in the diabetic patient group (P c Ͻ 0.01; P c = P value after Bonferroni correction) than in the control population. The MICA microsatellite allele consisting of four repetitions (A4) was present at a higher frequency in diabetic patients (P Ͻ 0.05). This deviated distribution was not changed even after controlling for the HLA DRB1-DQB1 haplotype. Transmission/disequilibrium test revealed significant deviation of transmission for alleles at the A6 polymorphism within the MICA gene (P Ͻ 0.05).CONCLUSIONS -We could assess that the MICA gene might be associated with type 1 diabetes transracially independent of the HLA gene.

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Genetic Structure of IDDM1: Two Separate Regions in the Major Histocompatibility Complex Contribute to Susceptibility or Protection

Cited by 52 publications

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Conditional ETDT analysis of the Human Leukocyte Antigen region in type 1 diabetes

Conditional ETDT analysis of the Human Leukocyte Antigen region in type 1 diabetes

Conserved extended haplotypes discriminate HLA-DR3-homozygous Basque patients with type 1 diabetes mellitus and celiac disease

MICA Polymorphism Is Associated With Type 1 Diabetes in the Korean Population

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